MOLECULAR GENETIC STUDIES OF BRANCHIO-OTO-RENAL SYNDROME

臂耳肾综合征的分子遗传学研究

• 批准号: 6238228
• 负责人: Shrawan Kumar
• 金额: $ 16.43万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6238228
• 关键词: CpG islands; artificial chromosomes; autosomal dominant trait; clinical research; congenital deafness; genetic polymorphism; human genetic material tag; human subject; linkage mapping; molecular cloning; molecular genetics

Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant disorder which consists of external, middle and inner ear malformations, branchial cleft sinuses, cervical fistulas, mixed hearing loss and renal anomalies. Variable clinical expression between families suggests that multiple gene loci are involved in causing the disease. Through genetic linkage analysis, the BOR gene has been localized on chromosome 8q. The purpose of the proposed study is to reduce the localization region to 0.5 to l cM and complete a YAC contig in the critical region to identify the BOR gene. The isolation of random human DNA sequences from the YACs will provide a set of closely spaced sequence tagged sites (STSs) which can be used to construct a framework map. This can be used to verify the existing physical map and help to fill the gaps between sets of contiguous clones. Gaps will be filled by walking out from known contiguous segments. Clones will be screened for di-, tri- and tetra- repeat polymorphisms and linkage will be used to refine the position of the BOR gene to the smallest possible region of chromosome 8q. YACs or their derivative cosmid subclones can be used as a resource to identify candidate genes in the region based on their possible association to CpG islands, by displaying evolutionary conserved DNA sequences, or by hybridization to tissue specific cDNA libraries and/or by exon trapping. The BOR gene will be identified among the candidate genes on the basis of its position, tissue specific expression and consistent mutation in affected individuals. Additional families will be required to narrow down the BOR region to the smallest interval. New families will be ascertained and tested for linkage with the markers on chromosome 8q. The possibility of genetic heterogeneity will be explored using the program HOMOG and unlinked families will be put through another round of genome searching to determine the location of new BOR-related genes. Clinical differences between families will be analyzed to determine to what degree they are correlated with different linkage groups. The BOR syndrome results in branchial, auditory, and renal abnormalities in affected individuals and poses serious health problems. Identification of the BOR gene(s) is the first and foremost step to a more comprehensive understanding of the pathogenesis and etiology of this syndrome. Finding the gene(s) will lay the foundation for further research concerning effective treatment and genetic counseling.

Branchio-Oto-Renal综合征(BOR)是一种常染色体显性遗传性疾病 包括外耳、中耳和内耳畸形、颧裂 鼻窦、颈瘘、混合性听力损失和肾脏畸形。 家系间不同的临床表达提示多基因 基因座与致病因素有关。通过遗传连锁 经分析，Bor基因已定位在染色体8q上。目的 建议的研究是将本地化区域缩小至L厘米至0.5厘米和 在关键区域完成YAC重叠群以鉴定Bor基因。这个 从YAC中分离随机的人类DNA序列将提供一组 紧密间隔的序列标记位点(STSS)可用于 构建框架地图。这可用于验证现有的 物理映射并帮助填补相邻克隆集之间的空白。 空白将通过退出已知的连续部分来填补。克隆人 将筛查二、三和四重复序列的多态和连锁 将被用来将Bor基因的位置细化到最小 染色体8q的可能区域。YAC或其衍生的粘粒 亚克隆可以作为一种资源来识别候选基因。 基于它们可能与CpG岛屿的关联的区域，通过显示 进化保守的DNA序列，或通过与组织杂交 特异性cDNA文库和/或外显子捕获。Bor基因将是 根据其位置、组织在候选基因中进行鉴定 在受影响的个体中具有特异性表达和一致突变。 将需要更多的家庭将Bor地区缩小到 最小间隔。新的家系将被确定并进行连锁测试 这些标记位于染色体8q上。基因突变的可能性 异质性将使用程序Homog和Unlink进行探索 家庭将接受新一轮的基因组搜索，以 确定新的Bor相关基因的位置。临床差异 将对家庭之间的关系进行分析，以确定他们在多大程度上 与不同的连锁群相关。 Bor综合征导致鳃、听觉和肾脏的异常 并对受影响的个人造成严重的健康问题。鉴定 博尔基因(S)的出现是迈向更全面的第一步 对本综合征的发病机制和病因的认识。查找 该基因(S)将为进一步的研究奠定基础。 有效的治疗和遗传咨询。